ObjectiveLiver fibrosis constitutes a major health problem worldwide due to its rapidly increasing prevalence and the lack of specific and effective treatments. Growing evidence suggests that signalling through cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways regulates liver fibrosis and regeneration. Rilpivirine (RPV) is a widely used anti-HIV drug not reported to produce hepatotoxicity. We aimed to describe the potential hepatoprotective effects of RPV in different models of chronic liver injury, focusing on JAK-STAT signalling regulation.DesignThe effects of RPV on hepatic steatosis, inflammation and fibrogenesis were studied in a nutritional mouse model of non-alcoholic fatty liver disease, carbon tetrachloride-induced fibrosis and bile duct ligation-induced fibrosis. Primary human hepatic stellate cells (hHSC) and human cell lines LX-2 and Hep3B were used to investigate the underlying molecular mechanisms.ResultsRPV exerted a clear anti-inflammatory and antifibrotic effect in all the in vivo models of liver injury employed, and enhanced STAT3-dependent proliferation in hepatocytes and apoptosis in HSC through selective STAT1 activation. These results were reproduced in vitro; RPV undermined STAT3 activation and triggered STAT1-mediated pathways and apoptosis in HSC. Interestingly, this selective pro-apoptotic effect completely disappeared when STAT1 was silenced. Conditioned medium experiments showed that HSC apoptosis activated STAT3 in hepatocytes in an interleukin-6-dependent mechanism.ConclusionRPV ameliorates liver fibrosis through selective STAT1-dependent induction of apoptosis in HSC, which exert paracrinal effects in hepatocytes, thus promoting liver regeneration. RPV’s actions may represent an effective strategy to treat chronic liver diseases of different aetiologies and help identify novel therapeutic targets.

A specific dual drug-induced mitochondria-ER effect enhances the MAMs content of Lon and its extramitochondrial expression. This is the first report of this phenomenon and suggests a novel MAMs-linked function of Lon protease.

Liver fibrosis (LF) occurs as a result of persistent liver injury and can be defined as a pathologic, chronic, wound‐healing process in which functional parenchyma is progressively replaced by fibrotic tissue. As a phenomenon involved in the majority of chronic liver diseases, and therefore prevalent, it exerts a significant impact on public health. This impact becomes even more patent given the lack of a specific pharmacological therapy, with LF only being ameliorated or prevented through the use of agents that alleviate the underlying causes. Hepatic stellate cells (HSCs) are fundamental mediators of LF, which, activated in response to pro‐fibrotic stimuli, transdifferentiate from a quiescent phenotype into myofibroblasts that deposit large amounts of fibrotic tissue and mediate pro‐inflammatory effects. In recent years, much effort has been devoted to understanding the mechanisms through which HSCs are activated or inactivated. Using cell culture and/or different animal models, numerous studies have shown that autophagy is enhanced during the fibrogenic process and have provided specific evidence to pinpoint the fundamental role of autophagy in HSC activation. This effect involves – though may not be limited to – the autophagic degradation of lipid droplets. Several hepatoprotective agents have been shown to reverse the autophagic alteration present in LF, but clinical confirmation of these effects is pending. On the other hand, there is evidence that implicates autophagy in several anti‐fibrotic mechanisms in HSCs that stimulate HSC cell cycle arrest and cell death or prevent the generation of pro‐fibrotic mediators, including excess collagen accumulation. The objective of this review is to offer a comprehensive analysis of published evidence of the role of autophagy in HSC activation and to provide hints for possible therapeutic targets for the treatment and/or prevention of LF related to autophagy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

In our model, p62 exerted a specific, autophagy-independent role and protected against efavirenz-induced mitochondrial ROS generation and activation of the NLRP3 inflammasome. These findings add to the multifunctional nature of p62 and may help to understand the off-target effects of clinically useful drugs.

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Due to medical advances over the past few decades, human immunodeficiency virus (HIV) infection, once a devastatingly mortal pandemic, has become a manageable chronic condition. However, available antiretroviral treatments (cART) cannot fully restore immune health and, consequently, a number of inflammation-associated and/or immunodeficiency complications have manifested themselves in treated HIV-infected patients. Among these chronic, non-AIDS (acquired immune deficiency syndrome)-related conditions, liver disease is one of the deadliest, proving to be fatal for 15–17% of these individuals. Aside from the presence of liver-related comorbidities, including metabolic disturbances and co-infections, HIV itself and the adverse effects of cART are the main factors that contribute to hepatic cell injury, inflammation, and fibrosis. Among the molecular mechanisms that are activated in the liver during HIV infection, apoptotic cell death of hepatocytes stands out as a key pathogenic player. In this review, we will discuss the evidence and potential mechanisms involved in the apoptosis of hepatocytes induced by HIV, HIV-encoded proteins, or cART. Some antiretroviral drugs, especially the older generation, can induce apoptosis of hepatic cells, which occurs through a variety of mechanisms, such as mitochondrial dysfunction, increased production of reactive oxygen species (ROS), and induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR), all of which ultimately lead to caspase activation and cell death.

The activity of sirtuin 1 (SIRT1), a class III histone deacetylase with a critical role in several biological functions, decreases with age and its deficiency is associated with many inflammatory and age-related diseases. It also regulates the chronic immune activation and viral latency during an HIV infection. The life-span and particularly the health span of HIV patients are substantially shortened; however, the participation of SIRT1 in these effects is not clear. We performed a prospective cross-sectional monocentric study that included 70 HIV-infected patients and 43 BMI-, age- and sex-matched uninfected individuals. We found that in the PBMCs of the HIV patients, SIRT1 mRNA levels were significantly lower (p < 0.0001). This decrease, which was corroborated at the protein level, occurred irrespectively of the antiretroviral regimen these patients received and was not significantly related to the general, HIV-related or comorbidity-related parameters. The levels of the major mitochondrial sirtuin SIRT3 were not altered. Moreover, the strong correlations of SIRT1 with the leukocyte markers CD8A and CD19 present in the uninfected individuals were absent in the HIV patients. In conclusion, this study showed that the PBMCs of the HIV patients displayed diminished SIRT1 levels and altered correlations of SIRT1 with markers of CD8+ T cells and B cells, findings which may be relevant for understanding the complex pathogenic milieu in HIV patients.

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